System for monitoring and delivering medication to a patient and method of using the same to minimize the risks associated with automated therapy

ABSTRACT

A system and method for monitoring and delivering medication to a patient includes a controller that has a control algorithm and a closed loop control that monitors the control algorithm. A sensor is in communication with the controller and monitors a medical condition. A rule base application in the controller receives data from the sensor and the closed loop control and compares the data to predetermined medical information to determine the risk of automation of therapy to the patient. The controller then provides a predetermined risk threshold where below the predetermined risk threshold automated closed loop medication therapy is provided. If the predetermined risk threshold is met or exceeded, automated therapy adjustments may not occur and user/clinician intervention is requested.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to a system for monitoring and delivering medication to a patient. More specifically, the present invention is directed toward a device that monitors the risk to a patient of allowing an automated therapy decision and allows a clinician to customize rules that determine whether an automated change in therapy is to be allowed or whether user/clinician intervention should be required based upon the risk of automation and the customized rules.

Diabetes is a metabolic disorder that afflicts tens of millions of people throughout the world. Diabetes results from the inability of the body to properly utilize and metabolize carbohydrates, particularly glucose. Normally, the finely tuned balance between glucose in the blood and glucose in bodily tissue cells is maintained by insulin, a hormone produced by the pancreas which controls, among other things, the transfer of glucose from blood into body tissue cells. Upsetting this balance causes many complications and pathologies including heart disease, coronary and peripheral artery sclerosis, peripheral neuropathies, retinal damage, cataracts, hypertension, coma, and death from hypoglycemic shock.

In patients with insulin-dependent diabetes the symptoms of the disease can be controlled by administering additional insulin (or other agents that have similar effects) by injection or by external or implantable insulin pumps. The correct insulin dosage is a function of the level of glucose in the blood. Ideally, insulin administration should be continuously readjusted in response to changes in blood glucose level. In diabetes management, insulin enables the uptake of glucose by the body's cells from the blood. Glucagon acts opposite to insulin and causes the liver to release glucose into the blood stream. The basal rate is the rate of continuous supply of insulin provided by an electronic medication (insulin) delivery device (pump). The bolus is the specific amount of insulin that is given to raise blood concentration of the insulin to an effective level when needed (as opposed to continuous).

Presently, systems are available for continuously monitoring blood glucose levels by inserting a glucose sensitive probe into the patient's subcutaneous layer or vascular compartment or by periodically drawing blood from a vascular access point to a sensor. Other measurement systems provide a continuous or periodic glucose measurement by noninvasively interfacing a patient with an optical or electromagnetic system. Such probes measure various properties of blood or other tissues including optical absorption, electrochemical potential, and enzymatic products. The output of such sensors can be communicated to a hand held device that is used to calculate an appropriate dosage of insulin to be delivered into the blood stream in view of several factors such as a patient's present glucose level and rate of change, insulin administration rate, carbohydrates consumed or to be consumed, steroid usage, renal and hepatic status, and exercise. These calculations can then be used to control a pump that delivers the insulin either at a controlled basal rate or as a periodic or one-time bolus. When provided as an integrated system the continuous glucose monitor, controller, and pump work together to provide continuous glucose monitoring and insulin pump control.

Such systems at present require intervention by a patient or clinician to calculate, control and confirm the amount of insulin to be delivered. However, there may be periods when the patient or clinician is not able to adjust insulin delivery or confirm recommended therapy decisions. For example, when the patient is sleeping, he or she cannot intervene in the delivery of insulin—yet control of a patient's glucose level is still necessary. A system capable of integrating and automating the functions of glucose monitoring and controlled insulin delivery would be useful in assisting patients in maintaining their glucose levels, especially during periods of the day when they are unable to intervene.

Alternately, in the hospital environment an optimal glucose management system involves frequent adjustments to insulin delivery rates in response to the variables previously mentioned. However, constant intervention on the part of the clinician is burdensome and most glucose management systems are designed to maximize the time interval between insulin updates. A system capable of safely automating low-risk decisions for insulin delivery would be useful in improving patient insulin therapy and supporting clinician workflow.

Since the year 2000 at least five continuous or semi-continuous glucose monitors have received regulatory approval. In combination with continuous subcutaneous insulin infusion (CSII), these devices have promoted research toward closed loop systems which deliver insulin according to real time needs as opposed to open loop systems which lack the real time responsiveness to changing glucose levels. A closed loop system, also called the artificial pancreas, consists of three components: a glucose monitoring device such as a continuous glucose monitor (CGM) that measures subcutaneous glucose concentration (SC); a titrating algorithm to compute the amount of analyte such as insulin and/or glucagon to be delivered; and one or more analyte pumps to deliver computed analyte doses subcutaneously. Several prototype systems have been developed, tested, and reported based on evaluation in clinical and simulated home settings. This concerted effort promises accelerated progress toward home testing of closed loop systems.

Similarly, closed loop systems have been proposed for the hospital setting and investigational devices have been developed and tested, primarily through animal studies. In addition, several manufacturers are either in the process of developing or have submitted to the FDA automated glucose measurement systems designed for inpatient testing. Such systems will accelerate the development of fully automated systems for inpatient glucose management.

The primary problem with closed loop control or full automation of insulin therapy is that a computerized system makes decisions that may be high risk in terms of potential consequences if the patient's condition changes or differs from the assumptions behind the computerized decision system. As a result of the automation these high risk decisions are not uncovered until the risk is realized and the patient displays an unacceptable medical condition. Second, in scenarios in which frequent glucose measurements are automatically collected but automation is not desired, it is undesirable to update the infusion at the same frequency as glucose measurements are collected. Third, when user intervention is required it may be undesirable or difficult for a clinician to respond at the bedside. For example, if the patient is in an isolation room but is observable, the clinician may desire to update the infusion rate without entering the room.

Thus, a principle object of the present invention is to provide an improved system for monitoring and delivering medication to a patient that makes risk determinations of an automated therapy decision and action before providing or continuing to provide automated therapy.

Yet another object of the present invention is to provide a system for monitoring and delivering medication to a patient that minimizes the risk to a patient based on automation of therapy.

Yet another object of the present invention is to provide a system for monitoring and delivering medication that is able to selectively request user intervention based upon a risk of automation of therapy.

Yet another object of the present invention is to provide a system for monitoring and delivering medication that allows a user to define an acceptable level of risk of automated therapy.

Yet another object of the present invention is to provide a system for monitoring and delivering medication that allows a user to define an unacceptable level of risk of automated therapy at or above which manually intervention is required.

These and other objects, features, or advantages of the present invention will become apparent from the specification and claims.

SUMMARY OF THE INVENTION

A system for monitoring and delivering medication to a patient and the method of using the same includes a controller that has an adjustment or control algorithm and an automation risk monitor that monitors the control algorithm. More specifically, the present invention is directed toward a system and method that monitors the risk to a patient of an automated therapy decision and allows a clinician to customize rules that determine whether an automated change in therapy or continuation of automated medication delivery therapy is to be allowed or whether user/clinician intervention should be required based upon the risk of automation and the customized rules. The customized rules may be established by the supplier of the system or by the user of the system. Thus, the risk of potential adverse consequences to the patient if the patient's condition changes or differs from the assumptions behind the computerized or automated decision system can be minimized.

A sensor in communication with the controller monitors a medical condition to provide data to a rule based application in the controller. In addition, the rule based application receives data, which may include monitored, measured or calculated values, from the closed loop control and compares the data to predetermined medical information to determine the risk of therapy automation to the patient. When the risk is below a predetermined risk threshold, medication or automated therapy adjustments are allowed to occur in an automated manner according to a closed loop algorithm. Alternatively, when the risk is above the predetermined risk threshold, the controller triggers a request for user intervention or reduces the degree of automated therapy allowed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a closed loop control system augmented with the automation risk monitor of the present invention;

FIG. 2 is an example messaging diagram for the present invention;

FIG. 3 is a schematic diagram showing the architecture of a semi-automatic glucose management system; and

FIG. 4 is a schematic diagram of an automation risk monitor system.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

FIG. 1 provides a system 10 for monitoring and delivering medication, such as insulin, to a patient 12. The system 10 includes a controller 14 that utilizes a control algorithm and an automation risk monitor 15 all presented in a closed loop. A sensor 16 is in communication with the controller 14 and monitors a medical condition of the patient 12. A rule based application 18 in the control receives data from the sensor 16 and compares the data to predetermined medical information to determine the risk to the patient 12 to automate the delivery of medication. The rule based application 18 in one embodiment includes physician or clinician entered conditions of when automation is acceptable. The system 10 is thus in communication with a clinician messaging system 20 that communicates to a clinician when the risk of automation is unacceptable. In a preferred embodiment the messaging system is remote from the system 10.

The rule based application 18 in one embodiment can include a risk profile wherein a clinician implements a risk profile according to a metric that may be qualitative (low, medium or high) or quantitative (1-10 where 10 is the highest risk) and a threshold defining when intervention is required. In either case, a quantitative metric is internally calculated and compared to a quantitative threshold. For example, in the case of low, medium or high each qualitative measurement is assigned a quantitative value such as 2, 5 and 7 respectively. Consequently, a risk scale is specified and a threshold is defined at or above which intervention is requested. The rule based application 18 can also include a risk matrix that is developed to enable a determination of risk. Although the matrix is ultimately stored internally, it can be parameterized by the user. One example of the risk matrix is shown below:

Glucose Range Glucose Change Calculated Change Risk (mg/dL) (derivative) in Insulin Level  0-70 Increasing Increasing High  0-70 Increasing Decreasing Low  0-70 Decreasing Increasing High  0-70 Decreasing Decreasing Low 70-90 Increasing Increasing Medium 70-90 Increasing Decreasing Low 70-90 Decreasing Increasing High 70-90 Decreasing Decreasing Low  90-120 Increasing Increasing Medium  90-120 Increasing Decreasing Low  90-120 Decreasing Increasing High  90-120 Decreasing Decreasing Low 120-180 Increasing Increasing Low 120-180 Increasing Decreasing Low 120-180 Decreasing Increasing Medium 120-180 Decreasing Decreasing Low 180-250 Increasing Increasing Low 180-250 Increasing Decreasing High 180-250 Decreasing Increasing Medium 180-250 Decreasing Decreasing Low Above 250 Increasing Increasing High Above 250 Increasing Decreasing Low Above 250 Decreasing Increasing Low Above 250 Decreasing Decreasing Medium

Specifically, the second column is the calculated or requested insulin level from the closed loop controller. The table is an example of how the treatment condition is mapped to a risk level. There are numerous other methods for implementing this information which may include continuous mapping functions, fuzzy logic, probabilistic models (e.g., Bayesian networks), probability calculations and the like.

A second way to provide this type of system is to employ an insulin/glucose pharmacokinetic/pharmacodynamic model as shown below which predicts the future glucose level and current insulin-on-board. The clinician can then use a predicted value and/or the anticipated insulin effect rather than or in addition to glucose level and a derivative.

$\begin{matrix} {{{\overset{.}{G}(t)} = {{{- p_{G}} \cdot {G(t)}} - {{S_{I}(t)} \cdot G \cdot \frac{Q(t)}{1 + {\alpha_{G}{Q(t)}}}} + \frac{{P(t)} + {EGP} - {CNS}}{V_{G\;}}}}{{\overset{.}{I}(t)} = {{{- n}\;\frac{I(t)}{1 + {\alpha_{I}{I(t)}}}} + \frac{u_{ex}(t)}{V_{I}} + \frac{u_{en}(t)}{V_{I}}}}{{{\overset{.}{P}}_{1}(t)} = {{{- d_{1}}{P_{1}(t)}} + {P_{e}(t)}}}{{{\overset{.}{P}}_{2}(t)} = {{- {\min\left( {{d_{2}{P_{2}(t)}},P_{m\;{ax}}} \right)}} + {d_{1}{P_{1}(t)}}}}{{P(t)} = {{\min\left( {{d_{2}{P_{2}(t)}},P_{m\;{ax}}} \right)} + {P_{N}(t)}}}{\overset{.}{G}(t)} = {{{- {p_{G}(t)}}{G(t)}} - {{S_{1}(t)}{G(t)}\;\frac{Q(t)}{1 + {\alpha_{G}{Q(t)}}}} + \frac{P(t)}{V_{G}}}} & (1) \\ {{{\overset{.}{Q}(t)} = {{- {{kQ}(t)}} + {{kI}(t)}}}{{\overset{.}{I}(t)} = {{{- n}\;\frac{I(t)}{1 + {\alpha_{I}(t)}}} + \frac{u_{ex}(t)}{V_{I}}}}} & (2) \end{matrix}$

In Equations (1)-(3), G(t) [mmol/L] denotes the total plasma glucose concentration, and I(t) [mU/L] is the plasma insulin concentration. The effect of previously infused insulin being utilized over time is represented by Q(t) [mU/L], with k [1/min] accounting for the effective life of insulin in the system. Exogenous insulin infusion rate is represented by Uex (t) [mU/min], whereas P(t) [mmol/L min] is the exogenous glucose infusion rate. Patient's endogenous glucose removal and insulin sensitivity through time are described by PG(t) [1/min] and WO [L/mU min], respectively. The parameters V_(I) [L] and V_(G) [L] stand for insulin and glucose distribution volumes. n [1/min] is the first order decay rate of insulin from plasma. Two Michaelis-Menten constants are used to describe saturation, with α_(I) [L/mU] used for the saturation of plasma insulin disappearance, and α_(I) [L/mU] for the saturation of insulin-dependent glucose clearance.

Thus, the rule base application 18 determines the risk of therapy automation to a patient 12 by referencing or comparing the monitored, measured, or determined present or future condition to a predetermined risk threshold. Below the predetermined risk threshold, because a low risk condition is detected, the system 10 can move forward in an automated fashion and provide medication as required. If the risk is determined to meet or exceed (i.e., be at or above) the predetermined risk threshold, the controller triggers a request for user intervention by contacting the clinician, for example via a clinician messaging system 20, instead of moving forward with automation.

In operation, the system 10 monitors a control algorithm of a controller 14 to receive data. The controller 14 additionally receives continuous data from a sensor 16 regarding a medical condition such as a glucose level. The controller 14 then compares the data from the control algorithm and the sensor 16 to predetermined medical information so that the controller 18 can determine whether a predetermined risk threshold of automating the delivery of medication has been met or exceeded. Then, based on the data, if a risk of automated therapy is below a predetermined threshold, automation is permitted and a command or request for medication or insulin is provided to the electronic insulin pump and the insulin delivery rate is automatically updated. Therefore the insulin delivery rate is automatically updated according to the algorithm model or closed loop controller used. Alternatively, if the risk is above a predetermined threshold, a request for user intervention is triggered sending a message to the clinician, for example via a clinician messaging system 20, so that a user may intervene to make a determination regarding whether the medication should be provided. The request for intervention is generated and sent directly to the user through a messaging system that is bi-directional. The message system 20 provides information and requests a user response. When the response is related to a change in therapy an authentication step is included.

The response to a request is provided by the user directly through the user interface of the system. Alternatively, the response can be returned through an authenticated messaging system involving a unique identifier specific to a positive or negative response.

During the course of normal operation glucose measurements may be received that generate a change in the recommended insulin. However, the change may not be significant enough to provide a therapeutic advantage to the patient versus the burden of requesting confirmation from the nurse. Consequently, a rule based system is provided which evaluates therapy changes to trigger a request for an automatic update or nursing intervention. The input to the rule based system includes the blood glucose level, the change in glucose, the insulin infusion, the recommended change in insulin infusion, the estimated insulin on board, and the predicted glucose in the future. Rules involving comparisons to thresholds, regression equations, and calculations are created which trigger a therapy update based on the inputs.

Thus, the present system can be used to make determinations of treatment decisions requiring user intervention based upon a diagnostic value, the change in diagnostic value, the current drug infusion rate, the updated drug infusion rate, and the treatment target range. In addition, the system notifies a clinician that intervention is required and receives the implementing clinician instruction in response to the notification.

An additional advantage is presented because the system 10 determines when clinician intervention is necessary and unnecessary. Specifically, system 10 is independent of an adaptive control algorithm or a computerized protocol. The system 10 functions as a safety supervisor that watches the performance of the closed loop system. Consequently, data from the closed loop system and diagnostic sensor 16 are provided to a rules database that uses a matrix to produce a quantitative level of risk of automation. The risk is compared to a particular risk threshold to either generate and/or provide an “okay” to proceed with automated therapy or to trigger a request for user intervention. The risk threshold can be selected or customized based on the desires of the user or the healthcare facility or organization.

This operation differs from current systems that do not determine risk of automation. Instead prior art systems allow automation to occur regardless of potential risk and then when sensors indicate a patient is experiencing an unacceptable medical condition a clinician is alerted. Therefore the system 10 provides an advantage of preventing the unacceptable medical condition from occurring in the first place as a result of monitoring the automation process, predetermining risks of automation, and comparing the risk of automation to a predetermined risk of automation threshold. The user can customize or select what factors are used to determine the risk of automation, as well as the predetermined threshold of automation risk that they are willing to accept without triggering a request for user intervention and preventing automated therapy. Thus, at the very least all of the stated objectives have been met. 

What is claimed is:
 1. A system for determining whether it is safe to operate a closed loop delivery of insulin to a patient, the system comprising: a controller; and a sensor in communication with the controller, said sensor configured to measure an indication of glucose in the patient; wherein the controller is configured to: provide a risk profile to a clinician for the patient, wherein the risk profile comprises a matrix including a plurality of risk levels for varying values of glucose, change in glucose, and change in insulin; receive an input from the clinician for each of the plurality of risk levels; receive measurements indicative of glucose in the patient from the sensor; determine a first trend corresponding to a change in insulin for the patient; determine a second trend corresponding to a change in the glucose measurements; apply rules on the received measurements, the first trend, and the second trend, wherein the rules include the risk profile that was parameterized by the clinician for when to exit closed loop delivery for the patient; determine whether it is safe to operate a closed loop delivery of insulin to the patient based on the application of rules; and prevent exit closed loop delivery of insulin and prompt user intervention based on the determination of safety using the application of rules.
 2. The system of claim 1, wherein the rules comprise an insulin-glucose model that predicts future glucose level and current insulin-on-board.
 3. The system of claim 1, wherein the rules comprises a matrix indicating a risk level based on a function of the received measurements, the first trend, and the second trend.
 4. The system of claim 1, wherein the rules comprise a Bayesian model of the received measurement, the first trend, and the second trend.
 5. The system of claim 1, wherein the controller is configured to determine that user intervention is not needed based on a recommended change in insulin infusion from the closed loop delivery.
 6. The system of claim 1, wherein the application of rules is further based on recommended change in insulin infusion from the closed loop delivery, the estimated insulin on board, and predicted glucose level in the future.
 7. The system of claim 1, wherein the controller is further configured to send a request for user intervention based on the determination of the safety using the application of rules.
 8. The system of claim 7, wherein the user intervention requires authentication.
 9. A method for determining whether it is safe to operate a closed loop delivery of insulin to a patient, the method comprising: measuring an indication of glucose in the patient with a sensor in communication with a controller; providing a risk profile to a clinician for the patient, wherein the risk profile comprises a matrix including a plurality of risk levels for varying values of glucose, change in glucose, and change in insulin; receiving an input from the clinician for each of the plurality of risk levels; receiving, at the controller, measurements indicative of glucose in the patient from the sensor; determining a first trend corresponding to a change in insulin for the patient; determining a second trend corresponding to a change in the glucose measurements; applying rules on the received measurements, the first trend, and the second trend; determining whether it is safe to operate a closed loop delivery of insulin to the patient based on the application of rules, wherein the rules include the risk profile configured to be parameterized by the clinician for when to exit closed loop delivery; and preventing exiting closed loop delivery of insulin and prompting user intervention based on the determination of safety using the application of rules.
 10. The method of claim 9, wherein the rules comprise an insulin-glucose model that predicts future glucose level and current insulin-on-board.
 11. The method of claim 9, wherein the rules comprises a matrix indicating a risk level based on a function of the received measurements, the first trend, and the second trend.
 12. The method of claim 9, wherein the rules comprise a Bayesian model of the received measurement, the first trend, and the second trend.
 13. The method of claim 9, further comprising determining that user intervention is not needed based on a recommended change in insulin infusion from the closed-loop delivery.
 14. The method of claim 9, wherein the application of rules is further based on recommended change in insulin infusion from the closed-loop delivery, the estimated insulin on board, and predicted glucose level in the future.
 15. The method of claim 9, further comprising sending a request for user intervention based on the determination of the safety using the application of rules.
 16. The method of claim 15, wherein the user intervention requires authentication. 